Thromboxane A₂ (TXA₂), the primary product of COX-I-dependent metabolism of arachidonic acid, mediates its biological actions through the TXA₂ receptor, termed the TP. Irreversible inhibition of platelet COX-I-derived TXA₂ with low-dose aspirin affords protection against primary and secondary vascular thrombotic events, underscoring the central role of TXA₂ as a platelet agonist in cardiovascular disease. The limitations associated with aspirin use include significant gastrointestinal toxicity, bleeding complications, potential interindividual response variability and poor efficacy in some disease states. This, together with the broad role of TXA₂ in cardiovascular disease beyond the platelet, has refocused interest towards additional TXA₂-associated drug targets, in particular TXA₂ synthase and the TP. The superiority of these agents over low-dose aspirin, in terms of clinical efficacy, tolerability and commercial viability, remain open questions that are the focus of ongoing research.